Pancreatic
Islets and Beta Cells

The pancreas is an organ about the size of a hand located in the
abdomen in the vicinity of the stomach, intestines, and other
organs. It lies behind the stomach and in front of the spine. The
pancreas produce juices that help digest food
and hormones such as insulin and glucagon that maintain
optimal blood sugar levels and help the body to use and store
energy from food.

Throughout the pancreas are clusters of cells called the islets
of Langerhans. Islets are made up of several types of cells,
including beta cells that make insulin. Insulin is a hormone that
helps the body use glucose for energy.

Insulin and Diabetes

Diabetes develops when the body doesn't make enough insulin,
cannot use insulin properly, or both, causing glucose to build up
in the blood. Diabetes is a serious disease, which, if not
controlled, can be life threatening. It is often associated with
long-term complications that can affect every system and part of
the body. Diabetes can contribute to eye disorders and blindness,
heart disease, stroke, kidney failure, amputation, and nerve
damage.

Type 1 Diabetes

Type 1 diabetes results from the body's failure to produce
insulin, the hormone that "unlocks" the cells of the body, allowing
glucose to enter and fuel them. It is an autoimmune disease in
which the body views the beta cells (insulin producing cells found
in the islets of the pancreas) as a foreign substance, so the
patient's immune system attacks the islets and kills them. It is
estimated that 5-10% of Americans who are diagnosed with diabetes
have type 1 diabetes. Most people with type 1 diabetes do not have
a family history of the disease and there is no way
currently to prevent the onset of type1 diabetes.

Insulin therapy, given by injection or insulin pump, is
life-saving. However, it's not perfect. Most people with type 1
diabetes still have blood glucose levels that are above normal.
This puts them at risk for the long-term complications of
diabetes.

Some people have what doctors call labile, or brittle, diabetes.
Blood glucose levels swing from high to low despite the best
insulin plans.

Because of this, long-term type 1 diabetic survivors often
develop vascular complications, such as diabetic retinopathy, an
eye disease that can cause poor vision and blindness, and diabetic
nephropathy, a kidney disease that can lead to kidney failure.

Hypoglycemia Unawareness

Those who are able to keep their blood glucose levels near
normal often have trouble with low blood glucose (hypoglycemia).
And after many years, some people lose the early symptoms that warn
them that their blood glucose level is dropping. This is called
hypoglycemia unawareness and raises the risk of severe
hypoglycemia.

Hypoglycemia unawareness is a life-threatening condition
that is not easily treatable with medication and is characterized
by reduced or absent warning signals for hypoglycemia. Some
Type 1 diabetic patients have been known to set their
alarms to wake them several times a night out of fear they may
have a catastrophic hypoglycemic episode while asleep. For such
individuals, transplantation of pancreatic islets is a viable
treatment option to consider.

Islet
Cell Transplantation Procedure

In islet transplantation, islets are taken from the pancreas of
a deceased organ donor. The islets are purified, processed, and
transferred into another person. Once implanted, the beta cells in
these islets begin to make and release insulin. Researchers hope
that islet transplantation will help people with type 1 diabetes
live without daily injections of insulin.

Researchers use specialized enzymes to remove islets from the
pancreas of a deceased donor. Because the islets are fragile,
transplantation occurs soon after they are removed. Typically a
patient receives at least 10,000 islet "equivalents" per kilogram
of body weight, extracted from two donor pancreases. Patients often
require two transplants to achieve insulin independence. Some
transplants have used fewer islet equivalents taken from a single
donated pancreas.

Transplants are often performed by a radiologist, who uses x
rays and ultrasound to guide placement of a catheter-a small
plastic tube-through the upper abdomen and into the portal vein of
the liver. The islets are then infused slowly through the catheter
into the liver. The patient receives a local anesthetic and a
sedative. In some cases, a surgeon may perform the transplant
through a small incision, using general anesthesia. Islets
extracted from a donor pancreas are infused into the liver. Once
implanted, the beta cells in the islets begin to make and release
insulin.

Image courtesy of University of Alberta and the
Clinical Islet Transplantation (CIT) Consortium, sponsored by
National Institute of Diabetes & Digestive & Kidney
Diseases (NIDDK) and National Institute of Allergy and
Infectious Diseases (NIAID)

Islets begin to release insulin soon
after transplantation. However, full islet function and new blood
vessel growth associated with the islets take time. The doctor will
order many tests to check blood glucose levels after the
transplant, and insulin is usually given until the islets are fully
functional.

Benefits and Risks Islet
Transplantation

Benefits

The goal of islet transplantation is to infuse enough islets to
control the blood glucose level without insulin injections. Other
benefits may include improved glucose control and prevention of
potentially dangerous episodes of hypoglycemia. Because good
control of blood glucose can slow or prevent the progression of
complications associated with diabetes, such as heart disease,
kidney disease, and nerve or eye damage, a successful transplant
may reduce the risk of these complications.

Risks

Risks of islet transplantation include the risks associated with
the transplant procedure-particularly bleeding and blood clots-and
side effects from the immunosuppressive drugs that transplant
recipients must take to stop the immune system from rejecting the
transplanted islets.

Most people need two infusions at different times to get enough
islets that are working, and some need three. So, even if islet
transplantation is found to be effective, currently, there are not
enough donor pancreases available to treat everyone with type 1
diabetes.

Immunosuppression and Rejection

As with any organ transplant, the recipient of an islet
transplant must take drugs every day to keep the body from
rejecting the islets. The immune system is programmed to
destroy bacteria, viruses, and tissue it recognizes as "foreign,"
including transplanted islets. In addition, the autoimmune response
that destroyed transplant recipients' own islets in the first place
can recur and attack the transplanted islets.

These drugs put the person at risk for infections and certain
cancers. They can also cause side effects that range from mild to
severe. Some people who received an islet transplant have had to
stop taking these medications, because of side effects and then
their new islets stopped working.

New
Immunosuppression Protocols

The Edmonton protocol introduced the use of a new combination of
immunosuppressive drugs, also called anti-rejection drugs,
including daclizumab (Zenapax), sirolimus (Rapamune), and
tacrolimus (Prograf). Daclizumab is given intravenously right after
the transplant and then discontinued. Sirolimus and tacrolimus, the
two main drugs that keep the immune system from destroying the
transplanted islets, must be taken for life or for as long as the
islets continue to function.

These drugs have significant side effects and their long-term
effects are still not fully known. Immediate side effects of
immunosuppressive drugs may include mouth sores and
gastrointestinal problems, such as stomach upset and diarrhea.
Patients may also have increased blood cholesterol levels,
hypertension, anemia, fatigue, decreased white blood cell counts,
decreased kidney function, and increased susceptibility to
bacterial and viral infections. Taking immunosuppressive drugs also
increases the risk of tumors and cancer.

Researchers continue to develop and study modifications to the
Edmonton protocol drug regimen, including the use of new drugs and
new combinations of drugs designed to help reduce destruction of
transplanted islets and promote their successful implantation.
These therapies may help transplant recipients achieve better
function and durability of transplanted islets with fewer side
effects. The ultimate goal is to achieve immune tolerance of the
transplanted islets, where the patient's immune system no longer
recognizes the islets as foreign. If achieved, immune tolerance
would allow patients to maintain transplanted islets without
long-term immunosuppression.

Researchers are also trying to find new approaches that will
allow successful transplantation without the use of
immunosuppressive drugs. For example, one study is testing the
transplantation of islets that are encapsulated with a special
coating designed to prevent rejection.

Shortage of Islets

A major obstacle to widespread use of islet transplantation is
the shortage of islets. Although organs from about 7,000 deceased
donors become available each year in the United States, fewer than
half of the donated pancreases are suitable for whole organ
pancreas transplantation or for harvesting of islets-enough for
only a small percentage of those with type 1 diabetes.

However, researchers are pursuing various approaches to solve
this problem, such as transplanting islets from a single donated
pancreas, from a portion of the pancreas of a living donor, or from
pigs. Researchers have transplanted pig islets into other animals,
including monkeys, by encapsulating the islets or by using drugs to
prevent rejection. Another approach is creating islets from other
types of cells, such as stem cells. New technologies could then be
employed to grow islets in the laboratory.

Note: The information above was reproduced or
derived from the following public domain
sources: The National Digestive Diseases Information
Clearinghouse (NDDIC) http://digestive.niddk.nih.gov/index.htm, the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) Reference Collection, and MedlinePlus, a service of
the National Library of Medicine and National Institutes of
Health (NIH), The Clinical Islet Transplantation (CIT) Consortium
is a network of clinical centers and a data coordinating center
established in 2004 to conduct studies of islet transplantation in
patients with type 1 diabetes, also funded by the NIH and NIDDK,
and Diabetes Education Online, UCSF Diabetes Teaching Center's
Diabetes Education Online.